Free Light Chain Monomer—Dimer Pattern Analysis as Non-Invasive Tool in Predicting MGUS and SMM Progression †

Background/Objectives: MGUS and smoldering multiple myeloma (SMM) are precursor states of plasma cell disorders with variable risk of progression to multiple myeloma (MM). Yet, current risk stratification models combine clinical and laboratory parameters, including invasive bone marrow assessment, but have limited precision. Methods: We applied free light chain (FLC)-monomer (M)–dimer (D) pattern analysis (FLC-MDPA), a non-invasive Western blot–based serum assay, to detect abnormal FLC M–D patterns associated with early malignant transformation, for predicting progression in MGUS (n = 68) and SMM (n = 40). Among 96 patients with complete data, 50 formed a training set to define criteria for progressive disease and 46 comprised a validation set. Results: FLC-MDPA predicted biochemical progression (sensitivity 0.79, specificity 0.92, NPV 0.86; HR 19.96, 95% CI 4.31–92) and clinical progression (sensitivity 0.84, specificity 0.79; HR 13.5, 95% CI 3.68–49.64), with significantly higher progression rates in patients with abnormal patterns (p < 0.0001). Within this high-risk cohort, FLC-MDPA was associated with higher hazard ratios for both biochemical and clinical progression compared with the 2/20/20 model, while incorporation into a modified 2/20/MDPA model improved sensitivity and negative predictive value. In a multivariable model including MDPA and FLC ratio, MDPA was independently associated with both clinical (p = 0.001) and biochemical progression (p = 0.04). Conclusions: These findings suggest that FLC-MDPA is a promising non-invasive tool for risk stratification in MGUS and SMM, improving sensitivity and negative predictive value while potentially reducing reliance on bone marrow–based assessment.